US10988473B2ActiveUtilityA1

Process for the preparation of (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-C]pyridine-5(4H)-carboxylate

Assignee: BENEVOLENTAI CAMBRIDGE LTDPriority: Oct 25, 2016Filed: Oct 25, 2017Granted: Apr 27, 2021

Est. expiryOct 25, 2036(~10.3 yrs left)· nominal 20-yr term from priority

Inventors:Viet-Anh Anne Horgan Olof Haglund Lee Patient Edward Savory Michael Higginbottom Michael Stewart Ashwood

C07D 471/04C07C 309/04C07B 2200/13A61K 31/437A61P 37/00A61P 43/00A61P 29/00

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Claims

Abstract

The invention relates to an improved process for the synthesis of (3S, 4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate, and pharmaceutically acceptable salts thereof, such as the methanesulphonic acid salt.

Claims

exact text as granted — not AI-modified

The invention claimed is: 
     
       1. A process for the preparation of (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate, or a pharmaceutically acceptable salt thereof, comprising:
 contacting (3S)-Tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(IV) with (R)-Mandelic acid (V): 
 
       
         
           
           
               
               
           
         
       
     
     
       2. The process according to  claim 1 , further comprising an additional crystallisation to obtain crystalline (3 S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (R)-Mandelate (VI): 
       
         
           
           
               
               
           
         
       
     
     
       3. The process according to  claim 2 , wherein the (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4,5-c]pyridine-5 (4H)-carboxylate (R)-Mandelate is obtained in
 (i) a yield of 20% or greater, 
 (ii) a purity of 80% or greater, and/or (iii) an enantiomeric excess (e.e.) of 95% or greater. 
 
     
     
       4. A compound comprising (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (R)-mandelate. 
     
     
       5. The compound according to  claim 4 , wherein the (3 S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4,5-c]pyridine-5 (4H)-carboxylate (R)-mandelate has
 (i) an e.e. of 95% or greater, and/or 
 (ii) a purity of 80% or greater. 
 
     
     
       6. A process for the preparation of (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4,5-c]pyridine-5 (4H)-carboxylate and pharmaceutically acceptable salts thereof using 4-Isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine dihydrochloride. 
     
     
       7. A process for the preparation of (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4,5-c]pyridine-5 (4H)-carboxylate and pharmaceutically acceptable salts thereof using (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(R)-mandelate. 
     
     
       8. The process according to  claim 1 , wherein the pharmaceutically acceptable salt is the mesylate salt. 
     
     
       9. A process for the preparation of (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5 (4H)-carboxylate mesylate from (3 S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (R)-mandelate. 
     
     
       10. A process according to  claim 9 , wherein
 (a) the (R)-mandelic acid is separated from the (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate by treatment with an alkaline agent, and then 
 (b) the (3 S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate is treated with methanesulphonic acid, 
 optionally comprising a crystallization to provide crystalline (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate mesylate, wherein the (3 S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate mesylate is obtained in a purity of 95% or greater; and/or 
 an e.e. of 95% or greater. 
 
     
     
       11. The process according to  claim 1 , wherein the (3 S)-tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4, 5-c]pyridine-5 (4H)-carboxylate(IV) is formed by coupling 4-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (II) or a dihydrochloride salt thereof and (S)-(+)-3-hydroxytetrahydrofuran (III) using a coupling agent to form (3S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4, 5-c]pyridine-5(4H)-carboxylate(IV): 
       
         
           
           
               
               
           
         
         wherein the coupling agent is N,N-disuccinimidyl carbonate. 
       
     
     
       12. The process according to  claim 11 , wherein the process comprises:
 reacting histamine (I) with isobutyraldehyde to form 4-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (II) or a dihydrochloride salt thereof 
 
       
         
           
           
               
               
           
         
       
       wherein the reaction to form 4-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (II) is maintained at a temperature of from 50 to 100° C. for a period of from 1 to 12 hours. 
     
     
       13. The process according to  claim 12 , wherein the reaction further comprises a solvent, and the solvent comprises ethanol, and/or the reaction is maintained at a temperature of refluxing ethanol,
 optionally, wherein in the process, the 4-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine dihydrochloride is isolated in 
 (i) a yield of 80% or greater; and/or 
 (ii) a purity of 95% or greater. 
 
     
     
       14. The process according to  claim 11 , wherein the coupling
 (i) is carried out in a solvent, and the solvent comprises dichloromethane; and/or 
 (ii) the reaction step comprises trimethylamine, 
 optionally wherein (3 S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate is obtained in a yield of 70% or greater and/or a purity of 80% or greater. 
 
     
     
       15. The process according to  claim 3 , wherein the (3 S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (R)-Mandelate is obtained in
 (i) a yield of 30% or greater, 
 (ii) a purity of 95% or greater, and/or 
 (iii) an enantiomeric excess (e.e.) of 99.9% or greater. 
 
     
     
       16. The compound according to  claim 5 , wherein the (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6, 7-dihydro-3H-imidazo[4, 5-c]pyridine-5 (4H)-carboxylate(R)-mandelate has
 (i) an e.e. of 99.9% or greater, and/or 
 (ii) a purity of 95% or greater. 
 
     
     
       17. The process according to  claim 10 , wherein
 the alkaline agent is an aqueous sodium hydrogen carbonate, and 
 optionally comprising a crystallization to provide crystalline (3S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate mesylate, wherein the (3 S,4S)-tetrahydrofuran-3-yl 4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate mesylate is obtained in a purity of 99.9% or greater; and/or 
 an e.e. of 99.9% or greater. 
 
     
     
       18. The process according to  claim 12 , wherein the 4-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (II) is the dihydrochloride, and optionally wherein the dihydrochloride is isolated. 
     
     
       19. The process according to  claim 12 , wherein the reaction to form 4-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (II) is maintained at a temperature of from 60 to 80° C. for a period of from 1 to 12 hours. 
     
     
       20. The process according to  claim 12 , wherein the reaction to form 4-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (II) is maintained at a temperature of from 50 to 100° C. for a period of from 5 to 7 hours.

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